Antibody therapies and diagnostics have been developed for use in treating a wide range of conditions including autoimmune diseases or disorders, infectious diseases, and cancers. Such therapies are useful but also can be undesirably immunogenic and damaging to healthy cells and tissues.
About 30% of all diagnosed leukemias are B-cell chronic lymphocytic leukemia (B-CLL), and the incidence of B-CLL is estimated to include 15,000 new cases and 4,500 deaths in the United States alone. Although generally considered incurable, a number of chemotherapies and biological therapies have been clinically tested in B-CLL patients. Of these, allogeneic hematopoietic stem cell transplantation (alloHSCT) may be the only curative treatment for some B-CLL patients. Boyiadzis et al., Expert Opin. Biol. Ther., 7: 1789-1797 (2007) and Gribben, J. G., Biol. Blood Marrow Transplant, 15: 53-58 (2008). AlloHSCT is believed to induce a graft-versus-leukemia (GVL) response in alloHSCT recipients. This GVL may be mediated by alloreactive donor T cells and/or donor B cell-derived allo-HSCT-induced antibodies. Bleakley et al., Nat. Rev. Cancer, 4: 371-380 (2004), Hambach et al., Curr. Opin. Immunol., 17: 202-210 (2005), and Wu et al., Adv. Immunol., 90: 133-173 (2006). Other clinically tested biological therapies include the use of rituximab and alemtuzumab. These therapeutic antibodies, however, target antigens found on both malignant and normal B cell surfaces. The CD52 antigen targeted by alemtuzumab is also expressed on the cell surface of a variety of other normal immune system cells. Accordingly, immunosupression can be a concern with such antibodies.
Strategies that have been used in attempts to identify antigens specific to malignant B-cells include differential gene expression profiling and SEREX analysis. SEREX involves using serum antibodies from cancer patients to screen recombinant cDNA expression libraries. These strategies, however, do not necessarily distinguish intracellular antigens from cell surface antigens.
There is a desire for additional antibody therapies that preferentially target malignant B cell surface antigens, have good efficacy, and are minimally immunogenic and/or damaging to non-diseased cells.